Vaccines are useful to immunize individuals against target immunogens such as pathogen antigens, allergens or antigens associated with cells involved in human diseases. Antigens associated with cells involved in human diseases include cancer-associated tumor antigens and antigens associated with cells involved in autoimmune diseases.
In designing such vaccines, it has been recognized that vaccines which produce the target antigen in the cell of the vaccinated individual are effective in inducing the cellular arm of the immune system. Specifically, live attenuated vaccines, recombinant vaccines which use a virulent vectors and DNA vaccines all lead to the production of antigens in the cell of the vaccinated individual which results induction of the cellular arm of the immune system. On the other hand, killed or inactivated vaccines and sub-unit vaccines which comprise only proteins do induce a humoral response but do not induce good cellular immune responses.
A cellular immune response is often necessary to provide protection against pathogen infection and to provide effective immune-mediated therapy for treatment of pathogen infection, cancer or autoimmune diseases. Accordingly, vaccines which produce the target antigen in the cell of the vaccinated individual such as live attenuated vaccines, recombinant vaccines which use a virulent vectors and DNA vaccines are preferred.
While such vaccines are often effective to immunize individuals prophylactically or therapeutically against pathogen infection or human diseases, there is a need for improved vaccines. There is a need for compositions and methods which produce an enhanced immune response.
Apart from prophylactic and therapeutic immunity, immune responses can be induced as a means to obtain compositions such as antibody compositions which include antibodies directed at a particular immunogen.
Gene therapy, in contrast to immunization, uses nucleic acid molecules that encode non-immunogenic proteins whose expression confers a therapeutic benefit to an individual to whom the nucleic acid molecules are administered. A specific type of gene therapy relates to the delivery of genetic material which encodes non-immunogenic proteins that modulate immune responses in the individual and thus confer a therapeutic benefit. For example, protocols can be designed to deliver genetic material which encodes non-immunogenic proteins that downregulate immune responses associated with an autoimmune disease in an individual and thus confer a therapeutic benefit to the individual. There is a need for compositions and methods which can be used in gene therapy protocols to modulate immune responses.
Modulation of immune responses by alternative means is similarly desirable to treat diseases such as autoimmune disease and cell/tissue/organ rejection. There is a need for compositions and methods which can be used to modulate immune responses and to design and discover compositions useful to modulate immune responses.
The direct introduction of a normal, functional gene into a living animal has been studied as a means for replacing defective genetic information. In some studies, DNA is introduced directly into cells of a living animal without the use of a viral particle or other infectious vector. Nabel, E. G., et al., (1990) Science 249:1285-1288, disclose site-specific gene expression in vivo of a beta-galactosidase gene that was transferred directly into the arterial wall in mice. Wolfe, J. A. et al., (1990) Science 247:1465-1468, disclose expression of various reporter genes that were directly transferred into mouse muscle in vivo. Acsadi G., et al., (1991) Nature 352:815-818, disclose expression of human dystrophin gene in mice after intramuscular injection of DNA constructs. Wolfe, J. A., et al., 1991 BioTechniques 11(4):474-485, which is incorporated herein by reference, refers to conditions affecting direct gene transfer into rodent muscle in vivo. Feigner, P. L. and G. Rhodes, (1991) Nature 349:351-352, disclose direct delivery of purified genes in vivo as drugs without the use of retroviruses.
The direct injection of DNA in both protective and therapeutic immunization protocols as well as non-immunogenic therapies is described in U.S. Pat. No. 5,593,972, U.S. Pat. No. 5,589,466, U.S. Pat. No. 5,830,876, U.S. Pat. No. 5,817,637, U.S. Pat. No. 5,981,505, U.S. Pat. No. 5,739,118, U.S. Pat. No. 5,962,428, U.S. Pat. No. 5,837,533, PCT/US90/01515, PCT/US93/02338, PCT/US93/048131, and PCT/US94/00899, which are each incorporated herein by reference. In addition to the delivery protocols described in those applications, alternative methods of delivering DNA are described in U.S. Pat. Nos. 4,945,050 and 5,036,006, which are both incorporated herein by reference. Essentially, gene constructs are delivered directly to individuals free of infectious agents such as replicating or non-replicating viral particles.
There remains a need for more effective compositions and methods of inducing immune responses and delivering therapeutic proteins.